Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
PMC full text:
J Bioenerg Biomembr. Author manuscript; available in PMC 2016 Apr 1.
Published in final edited form as:
J Bioenerg Biomembr. 2015 Apr; 47(0): 111–118.
Published online 2014 Sep 28. doi: 10.1007/s10863-014-9571-y

Fig 2

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Model of how idebenone interacts with electron transport chain complex I. The oxidation of NADH by complex I results in the transfer of two electrons to complex III via ubiquinone/coenzyme Q10 (Q), accompanied by the pumping of four protons (H+) from the mitochondrial matrix to the intermembrane space. Idebenone (IdB) competes with endogenous Q at the physiological hydrophobic quinone binding site for electrons from upstream iron-sulfur (FeS) clusters. The two-electron reduction of idebenone results in a product, idebenol (IdBH2), with very slow dissociation kinetics from the quinone binding site. This slow dissociation not only makes idebenol ineffective at electron transfer to complex III but also allows it to competitively inhibit the electron transfer to complex III that normally occurs via endogenous ubiquinol (QH2). A second interaction of idebenone with complex I occurs at a non-physiological hydrophilic quinone binding site that overlaps with the flavin mononucleotide (FMN) moiety. Here, the one electron reduction of idebenone yields an unstable semiquinone intermediate (IdBH·). This semiquinone causes the one-electron reduction of oxygen (O2) to superoxide (O2·-), regenerating idebenone. The net results of idebenone-complex I interactions are impaired complex I functionality and superoxide generation

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